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Organ distinctive mutagenicity in MutaMouse after short-term exposure to PhIP
A M Lynch1, N J Gooderham, A R Boobis
1Department of Clinical Pharmacology, Royal Postgraduate Medical School, London, UK.
Abstract:
We have investigated PhIP-induced mutagenicity in various tissues (kidney, liver, large and small intestine) using a transgenic mouse model (MutaMouse). In addition to tissue specific mutagenesis, we measured the binding of [14C]PhIP to MutaMouse mice blood proteins (haemoglobin and albumin), to obtain a quantitative estimate of carcinogen exposure and activation and their relationship to mutagenesis. Short-term (4 days) treatment of MutaMouse mice with [14C]PhIP by oral gavage resulted in the dose-dependent accumulation of radiolabelled material bound to haemoglobin and serum albumin. PhIP, at the highest dose (20 mg/kg), caused a 5.9-fold increase in the mutation frequency in the large intestine, a 4.2-fold increase in the mutation frequency in the small intestine but only a marginal 1.6-fold increase in the liver. However, there was no significant increase in mutations in the kidney at this dose. In contrast, there were no significant differences in any of these tissues between the vehicle control and the two lower doses (2.0 and 0.2 mg/kg respectively). These results are discussed in relationship to those previously reported for PhIP at the Dlb-1 locus.
Insights
This study shows that PhIP (a foodborne carcinogen) causes dose-dependent mutations in the large and small intestines of MutaMice. Kidney and liver tissues showed minimal mutagenic effects from PhIP exposure.
Area of Science:
- Toxicology
- Genetics
- Carcinogenesis
Background:
- PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) is a heterocyclic amine found in cooked meats.
- Exposure to PhIP has been linked to increased cancer risk.
- Understanding tissue-specific mutagenicity is crucial for risk assessment.
Purpose of the Study:
- To investigate the mutagenicity of PhIP in various tissues of the MutaMouse model.
- To correlate PhIP exposure levels with mutation frequency.
- To assess tissue-specific responses to PhIP.
Main Methods:
- Utilized a transgenic MutaMouse model for mutagenicity testing.
- Administered radiolabeled [14C]PhIP via oral gavage over a short-term period (4 days).
- Measured [14C]PhIP binding to blood proteins (hemoglobin and albumin) as a biomarker of exposure and activation.
- Assessed mutation frequency in kidney, liver, large intestine, and small intestine.
Main Results:
- Dose-dependent accumulation of radiolabeled PhIP-protein adducts in hemoglobin and albumin was observed.
- The highest PhIP dose (20 mg/kg) significantly increased mutation frequency in the large intestine (5.9-fold) and small intestine (4.2-fold).
- A marginal increase (1.6-fold) in liver mutation frequency was noted, with no significant increase in kidney mutations.
Conclusions:
- PhIP exhibits significant tissue-specific mutagenicity, primarily affecting the gastrointestinal tract.
- PhIP-protein adducts serve as reliable indicators of exposure and activation.
- Results highlight the importance of considering tissue distribution and metabolic activation in carcinogen risk assessment.